The liver has a unique adaptive response to continuous nutritional support (NS). The liver switches from a site of modest glucose uptake and glycogen storage to an organ that efficiently converts glucose to lactate (i.e. enhanced glycolytic capacity). As a consequence of this shift in hepatic metabolic flux we hypothesize the normal regulators of liver glucose uptake and disposition in the acute setting (glucose and insulin levels and route of glucose delivery) no longer exert the same degree of control in the adapted setting. We believe the fall in glucagon during NS is essential to allowing the adaptation to occur. The enhanced hepatic glucose disposition observed in the adapted setting decreases the fraction of the exogenous glucose removed by peripheral tissues, while still preserving total carbohydrate uptake (glucose + lactate) by peripheral tissues. Following chronic NS greater than &#8531;of the peripheral carbohydrate uptake is as lactate. Since lactate is more efficiently cleared than glucose and less dependent upon insulin for its removal and the absolute rate of glucose uptake by peripheral tissues is diminished, the insulin and glucose concentrations are decreased as well. Infection impairs this adaptive response despite compensatory hyperinsulinemia with the liver reverting back to a state similar to the un-adapted (i.e. acute) state. The failure to adapt shifts the responsibility of glucose removal to peripheral tissues. When combined with the infection induced peripheral insulin resistance the risk of developing hyperglycemia increases. We believe the infection induced rise in glucagon contributes to the impaired adaptive response and aggravates the peripheral insulin resistance. Moreover, while compensatory hyperinsulinemia and/or hyperglycemia or enteral glucose delivery can acutely correct the impairment in liver glucose uptake, we hypothesize this cannot be sustained because of the deficit in hepatic glycolytic capacity. The questions we will address are. Does the suppression of glucagon secretion play an essential role in facilitating the metabolic response to NS and does its failure to suppress during infection contribute to the abnormal hepatic and peripheral metabolism? What is the mechanism whereby glucagon inhibits muscle glucose uptake? Are the compensatory hyperinsulinemia and hyperglycemia during infection able to sustain the adaptive response to NS? Does infection impair the ability of portal and enteral glucose delivery to facilitate liver glucose uptake and inhibit peripheral glucose uptake during NS? Experiments will be carried out in chronically catheterized conscious dogs receiving continuous nutritional support. Hepatic glucose metabolism (unidirectional hepatic glucose uptake and production, glucose oxidation) and hindlimb will be assessed using a combination of tracer and arterio-venous difference techniques. While previous work has examined the response of whole body glucose metabolism to infection, our model provides the unique ability to directly examine the role that individual organs (liver and muscle) play in the infection-induced modulation of nutrient disposition and the factors responsible for the impairment and the mechanisms by which they occur. Project Description